Intracerebral hemorrhage (ICH) is the only form of stroke without a clearly defined treatment. It occurs in more than 100,000 Americans each year, with 30% to 50% mortality and significant motor and cognitive disabilities in the majority of survivors. Minorities bear an increased burden of disease. The severity of the injury is directly related to blood clot volume and time blood is exposed to brain. No trial has been organized to test the hypothesis that blood clot removal benefits the ICH stroke patient. The MISTIE trial is a proof of concept clinical trial with sufficient statistical power to provide a definitive evaluation of the safety and clinical benefit of image-based, minimally invasive surgery (MIS) to aspirate clot in combination with instillations of rt-PA following surgery for further clot dissolution. The trial is in two steps: Dose Optimization followed by a Safety Study. The study will be completed over 7 years, using an intent-to-treat analysis. The original goal and hypotheses are unchanged. The current results have already provided first-time data about rt-PA safety and clot dissolution, patient selection, patient stability, quantitation of MIS surgical effectiveness and definition of treatment related complications. The test surgery, MIS + rt-PA, was performed in 24 subjects with minimal mortality and acceptable morbidity compared to 6 control subjects. Seven of the original eight centers are performing the surgical procedure and the trial procedures effectively and enthusiastically. The surgical procedure has been graded as acceptable by the independent surgical center in 96% of the procedures performed. This surgery has led to substantial reduction of clot size in the majority of subjects. We have removed 50% or more of the clot in 83% of subjects (average volume removed 27 cc) and met the predetermined surgical removal goals in 62.5% of randomized subjects. The final safety and outcome results are pending completion of recruitment. These results will provide robust estimates of effect of MIS on outcome for ICH. The long-term goal of this research is to change the way ICH is treated, that is, to reduce brain injury with innovative and forward-looking minimally invasive surgical management. This type II funding proposal requests $2.9 million to sustain trial infrastructure to complete recruitment and test the original hypothesis. PUBLIC HEALTH RELEVANCE: Intracerebral hemorrhage (ICH) is the only form of stroke without an effective treatment. Intracerebral hemorrhage occurs in over 100,000 Americans each year. It is fatal in 30% to 50% of all occurrences and leaves the majority of the survivors with significant motor and cognitive disability. Minorities bear an increased burden of disease in ICH. Compared to ischemic stroke, ICH is easily and rapidly identified: it occurs in younger patients and initially produces a smaller injury to the cerebral tissues, suggesting that interventional amelioration is possible with the right treatment, such as image- guided, minimally invasive surgery. Yet, of the major stroke subtypes-ischemic, aneurysm rupture, and intracerebral hemorrhage-intracerebral hemorrhage is the only major subtype without a clearly defined treatment.